World-wide HIV infection rates remain remarkably high despite a thorough understanding of the epidemiological and behavioral risk factors for acquisition. These risk factors are of a diverse nature and include high risk sexual practices, geographical HIV prevalence, virus load in the transmitter, circumcision status and other sexually transmitted infections such as herpes simplex virus type 2 infection. However, the observation that in very similar risk settings only some persons become infected whereas others do not remains somewhat enigmatic. In this project we aim is to used novel precision GWAS approaches to discover host genomic polymorphisms that determine protection from and susceptibility to the acquisition of HIV. We performed a two-stage wholly NGS-based analysis of the high-risk HVTN 505 vaccine cohort as well as carefully matched HIV-infected persons from other cohorts. We used our dataset to explore the separate additional question of host genetic influence on vaccine efficacy in the HVTN 505 trial. We discovered multiple polymorphisms with very high significance that that determine protection from and susceptibility to HIV acquisition. We found that HVTN 505 was efficacious in 30% of the cohort with a specific genotype.